Download Clinical Reasoning in Oncology

Clinical Reasoning in Oncology
EVIDENCE-BASED MANAGEMENT OF
CANCER IN THE ELDERLY
Lodovico Balducci, MD
From the Senior Adult Oncology Program at the H. Lee Moffitt Cancer Center
& Research Institute at the University of South Florida, Tampa, Florida.
E-mail: [email protected]
Introduction
A discussion of evidence-based
management of cancer in the
elderly assumes an evidence-based
position that senescence is a distinct stage of human development
that affects the biology of cancer
as well as the goals, efficacy, and
tolerance of cancer treatment. This
article explores the levels of evidence supporting this assumption
in three areas: (1) clinical assessment of age, (2) age-related
changes in tumor biology, and (3)
age-specific issues related to cancer treatment. The levels of evidence are defined in Table 1.
Evidence Relating to
Assessment of Age
Age differences are apparent
in a series of pictures of the same
person over a year or in a family
portrait that includes members of
different generations. Yet, determining the onset of senescence or
defining a person’s physiologic age
in objective terms remains controversial. The aging process is composed of several stages1 that, from a
clinical standpoint, do not accurately differentiate young from old.
This differentiation is needed, however, to provide optimal care.
To address these issues from
an evidence-based standpoint, we
will examine the implications of
aging on which wide consensus
exists. These implications include
a progressive reduction in the life
expectancy2 and deterioration of
the functional reserve of different
organs and systems.3 Also, aging
generally is associated with
increasing prevalence of comorbid
conditions,2,4 disability,4 and a
group of disorders defined as “geriatric syndromes”5 (Table 2). The
Table 1. — Definition of Levels of Evidence
Level of Evidence
Definition
I
Supported by one or more randomized controlled trials
II
Supported by one or more retrospective studies or by one or
more cohort studies
III
Supported by clinical experience or review of case report
IV
Supported only by expert opinion
Table 2. — Geriatric Syndromes
Dementia
Delirium
(induced by drugs or by organ-confined infections not involving the central nervous system)
Depression
Falls (≥3 per month)
Fecal incontinence
Osteoporosis associated with spontaneous fractures
Failure to thrive
Presence of neglect and abuse
368 Cancer Control
July/August 2000, Vol. 7, No.4
Table 3. — Clinical Assessment of Functional Status, Comorbidity, and Geriatric Syndromes on Life Expectancy and Functional Reserve
Parameter
Correlation With
Life Expectancy
Correlation With
Declining Functional Reserve
Functional Status
2-year mortality doubles
with dependence in IADLs
and increases threefold with
dependence in ADLs.
Mortality of elderly hospitalized patients increases with
decline in functional status.
Life expectancy: II
Functional reserve: II
Reuben et al6
Manton7
Inouye et al8
Comorbidity:
- Number of comorbid
conditions
- Comorbidity index
Risk of non-cancer-related
death increases in breast
cancer patients with the
number of comorbid
conditions.
Patients with multiple
comorbid conditions or
with severe comorbidity
have increased surgical
mortality and are generally
excluded from clinical trials
and may receive reduced
doses of chemotherapy in
clinical practice.
Life expectancy: II
Functional reserve: II-III
Satariano and Regland9
Piccirillo et al10
Newschaffer et al11
Extermann12
Demented patients are
generally excluded from
chemotherapy trials.
Life expectancy:
II Functional reserve: IV
Eagles et al13
Flacker and Kiely14
Winograd et al15
Life expectancy: II
Functional reserve: IV
Covinsky et al16
Risk of cancer-related death
may increase as well with
the number of comorbid
conditions.
Level of Evidence
References
Risk of mortality is a function of a comorbidity index
measuring the seriousness
of comorbid conditions.
Cognition
Risk of mortality increases
with decline in minimental
status.
Depression
Depression is an independent prognostic factor for
mortality in elderly patients.
Falls
Falls are harbingers of
mortality.
Patients who fall frequently
are considered frail
Life expectancy: II
Functional reserve: IV
Tinetti and Williams17
Delirium
Short- and long-term mortality increases in patients
experiencing delirium during hospitalization or as a
result of medications and
infections.
Patients with a history of
delirium are considered
frail and incapable of
independent living.
Life expectancy: II
Functional reserve: III-IV
Inouye et al18
Fecal Incontinence
Increased mortality is
associated with fecal
incontinence.
Patients have serious
neurological or mental
problems.
Life expectancy: II
Functional reserve: IV
Rockwood et al19
Neglect and abuse
Mortality increases among
elderly subjected to neglect
and abuse.
Patient are incapable of
independent living.
Life expectancy: II-III
Functional reserve: IV
Mendonca20
July/August 2000, Vol. 7, No.4
Cancer Control 369
next step is to investigate whether
the clinical assessment of functional status, comorbidity, and geriatric
syndromes may reflect decreases in
life expectancy and functional
reserve. This issue has been
addressed by several authors over
the last decade. Recent results are
summarized in Table 3.6-20
Prospective and retrospective
studies have shown that functional
status, comorbidity, geriatric syndromes, and mortality are all correlated. Less clear is the correlation
between these parameters and
functional reserve. Perhaps the
major obstacle in establishing this
correlation is the absence of “gold
standards” for assessing functional
reserve. While the functional reserve of individual organs such as
the lung or kidney can be accurately assessed, a comprehensive
measurement of functional reserve
is lacking. Reduced functional
reserve may be inferred from
reduced ability of the body to cope
with stress. For example, mortality
from emergency surgery increases
two- to three-fold after age 70, suggesting that the elderly are less
equipped than younger individuals
to withstand severe stress.21 Likewise, a lack of independence in the
activities of daily living (ADLs)
predicts increased immediate and
6-month mortality for hospitalized
elderly patients.8,22 These data suggest a correlation between severe
functional impairment and functional reserve. However, in the
majority of cases, clinicians are
more interested in detecting early
limitations in functional reserve
that do not compromise daily function but may lead to decreased
370 Cancer Control
tolerance of cancer chemotherapy.
For this purpose, the information
is inadequate. It is possible that dependence in one or more instrumental activities of daily living
(IADLs) may provide a clue to these
lesser but clinically relevant restrictions in functional reserve.22-26
IADLs include shopping, use of
transportation, medication management, meal preparation, money
management, and housekeeping.
Extermann et al4 reported that the
prevalence of dependence in
IADLs was higher than 70% in a
population of cancer patients aged
70 and older who were studied at
our institute over 2 years. These
individuals tended to be relatively
healthy as they were well enough
to have been referred to a tertiary
cancer care center. BarbergerGateau et al23 showed that dependence in using transportation, managing finances, and taking medications correlated with the onset of
cognitive disorder. Monfardini et
al24 showed a correlation between
dependence in some IADLs and the
risk of complications from cytotoxic chemotherapy.
In recent years, a special component of older individuals has
been described — those who are
frail. The frail patient has a severely limited functional reserve and
generally is not a good candidate
for aggressive cancer treatment.
Commonly accepted criteria for
frailty are listed in Table 4.5 Age is
the most controversial factor
because many of the persons surviving in the 9th and 10th decade
of life are healthy with decreased
prevalence of oxidative stress and
arteriosclerosis.25,26 The population
Table 4. — Clinical Diagnostic Criteria
of Frailty
Age ≥ 85
Dependence in 1 or more activities of
daily living (ADLs)
Presence of 3 or more comorbid conditions
Presence of 1 or more geriatric syndromes
of the oldest old seems to be composed of at least two groups: (1)
those who are frail but have survived due to advances in medical
treatment and (2) those who have
survived because of inherited resistance to environmental insults;
these may or may not be frail. Thus,
in terms of treatment options, age
should be considered as one piece
of evidence rather than as a diagnostic criterion of frailty.
The claim that frailty is a distinct clinical condition is based on
level II evidence (dependence in
ADLs and comorbidity) and level III
evidence (all other criteria).8,22
Despite the limitations on the level
of evidence, the definition of frailty
serves an important clinical function in geriatric oncology: preventing harm from chemotherapy to a
particularly vulnerable group of
patients. For this population, it is
reasonable to expect the risks of
chemotherapy to outweigh its
potential benefits for the following
reasons:
• The shortened life expectancy
of frail patients limits survival benefit
from aggressive chemotherapy.
• Age is associated with increased risk of chemotherapy complications.27 Frail patients appear
to be the least fit of the aged and
July/August 2000, Vol. 7, No.4
thus are the most vulnerable to
therapeutic complications.
• Performance status is a predictor of chemotherapy toxicity in
younger patients. Frail patients
almost by definition have a poor
performance status.
ratio in the circulation.30 All of
these tests lack specificity and are
not sensitive to early age-related
changes. Likewise, clinical tests of
physical function should be considered experimental and of limited clinical applicability.31
• Substitute the number of
comorbid conditions with comorbidity indices that reflect the severity of the conditions.
In conclusion, the evidence
suggests that aging may be assessed
by a number of clinical parameters.
These parameters not only reflect
the individual’s life expectancy, but
also may reflect the individual’s
functional reserve to some extent.
A valid, well-substantiated definition of frailty will allow the identification of older patients whose
functional reserve is particularly
compromised. This definition may
be adjusted with further research.
• Grade the severity of some
geriatric syndromes (eg, dementia,
depression, osteoporosis).
Age-Related Changes in
Tumor Biology
There is the risk, however, that
too broad a definition of frailty may
prevent the treatment of patients
who may benefit from chemotherapy. The definition of frailty needs
clarification with hypothesis-driven
research as follows:
• Study the possibility that
one or more components of frailty
may be reversible. Of special concerns are situations in which an
older patient becomes functionally
dependent over a short period of
time. In these situations, the tumor
itself may be responsible for the
rapid functional decline, and
aggressive antineoplastic treatment may improve the patient’s
function.
• Establish reliable biochemical markers of aging. At present,
there are no reliable biochemical
markers of aging. Proposed markers include changes in creatinine
clearance,5 in plasma osmolality,28
in serum concentrations of interleukin 6,29 and in the cysteine/thiol
July/August 2000, Vol. 7, No.4
Level II evidence shows that
the prognosis of three malignancies — acute myelogenous leukemia,32,33 large-cell non-Hodgkin’s
lymphoma,34 and celomic ovarian
cancer35 — worsens with advancing patient age. The mechanisms of
these changes are only partly
understood and may involve
changes in the malignant cell (the
seed), the tumor host (the soil), or
both. In the case of acute myelogenous leukemia, the main determinant of poorer prognosis is the
presence of a more chemoresistant
disease in older patients. The
prevalence of myeloblasts expressing MDR-1 gene and of unfavorable
chromosomal abnormalities increases after age 60.36 In the case
of large-cell non-Hodgkin’s lym-
phoma, patient-related changes
may be responsible for a poorer
prognosis. The concentration of
circulating interleukin 6 (IL-6)
increases with the age of the
patient, and increased levels of IL-6
are a poor prognostic factor for
large-cell lymphoma.37 In the case
of breast cancer, level II evidence
suggests a more indolent disease38
characterized by well-differentiated, hormone-receptor-rich tumors.
However, it is not clear whether
age affects the overall prognosis.
Likewise, non-small cell lung cancer is more likely to present at an
early stage in older individuals, but
whether age affects the overall
prognosis is unclear.39
In conclusion, level II evidence
shows that the behavior and the
prognosis of some malignancies
may change with the age of the
patient. Age itself, however, is a
poor predictor of the course of a
particular neoplasm in a particular
patient. Research should include
identifying tumor markers of prognostic value (eg, the MDR-1 product or abnormalities of p53) and
patient markers (eg, circulating levels of IL-6 and other cytokines) in
older individuals.
Cytotoxic Chemotherapy
in the Older Cancer
Patient
It is reasonable to expect that
older persons may be more susceptible than younger persons to the
toxicity of cytotoxic chemotherapy, given the reduced functional
reserve of many organ systems and
the possible alterations in the pharCancer Control 371
macokinetics of drugs.3,27 This section examines the evidence related
to the following questions: Do the
complications of cytotoxic chemotherapy become more common
and more severe in the older
patient? Are there effective methods to ameliorate the toxicity of
chemotherapy in the elderly?
the toxicity of patients involved in
phase II studies at the Illinois Cancer Center, and Gelman and Taylor44 reported on the incidence of
myelotoxicity in breast cancer
patients treated with combination
chemotherapy for those 65 years
of age and older compared with
those under 65 years of age.
Five retrospective studies of
chemotherapy-induced toxicity40-44
failed to demonstrate a clear correlation between patient age and
the incidence and severity of therapeutic complications. Newcomb
and Carbone40 reviewed the 10year experience of the Eastern
Cooperative Oncology Group
(ECOG). Christman et al41 reviewed the experience of the
Piedmont Oncology Group studies
of metastatic breast cancer.
Ibrahim and colleagues42 reported
on the 20-year experience of the
University of Texas-M.D. Anderson
Cancer Center in the management
of metastatic breast cancer. Giovanazzi-Bannon et al43 reviewed
While these studies are important because they indicate that age
over 70 years does not inevitably
involve more serious complications of chemotherapy, they can
hardly be considered representative of the older population at
large for several reasons: (1) There
was a clear selection bias. In the
ECOG study,40 only 11% of patients
were over 70 years of age, while
the incidence of various cancers
treated suggests that 40% of the
patients should have been 70 years
of age or older. (2) Only a small
minority of patients were 75 years
of age or older, so the data are
skewed toward the so-called
“young old.” (3) The toxicity of
treatment protocols in use at the
time of these studies may not be
comparable with the toxicity of
more recent treatment protocols.
Based on a review of older
patients with large-cell nonHodgkin’s lymphoma45 (Table 5)
and with gastrointestinal malignancies treated by the Gastrointestinal Tumor Study Group,46
level II evidence suggests that the
incidence and severity of myelotoxicity and mucositis increase
with age. A close examination of
the lymphoma studies indicates
that in persons over age 70, the
incidence of neutropenia was
consistently higher than 50%44-49
and the incidence of treatmentrelated mortality in patients over
70 ranges between 5%47,48 and
30%.36 Most of the treatmentrelated mortality occurred during
the first course of chemotherapy.
This incidence of toxicity and
mortality is higher than that seen
in younger individuals undergoing
the same form of treatment.
Table 5. — Risk of Myelotoxicity in Older Individuals With Large-Cell Non-Hodgkin’s Lymphoma Treated With CHOP-Like Combination Chemotherapy
Author(s)
Regimen
Age
Grade III and IV Neutropenia
Treatment-Related Mortality
Zinzani et al47
VNCOP-B
65+
55%
-
Gomez et al48
CHOP
60-69
42%
0%
>69
100%
7%
49
Armitage and Potter
CHOP
70+
-
30%
Bastion et al53
CTVP
70+
55%
15%
CHOP, CNOP
60+
-
5%
CHOP, VMP
70+
55%
5%
Sonneveld et al54
Tirelli et al
55
VNCOP-B = cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, prednisone
CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone
CTVP = cyclophosphamide, teniposide, prednisone, pirarubicin
CNOP = cyclophosphamide, mitoxantrone, vincristine, prednisone
VMP = etoposide, mitoxantrone, prednimustine
372 Cancer Control
July/August 2000, Vol. 7, No.4
Table 6. — Current Recommendations to Ameliorate
Chemotherapy-Related Toxicity in Older Persons With Cancer
• Base patient selection on comprehensive geriatric assessment, with exclusion of frail patients
from aggressive forms of treatment and interventions aimed to restore nutrition and social
support and to control underlying diseases and disabilities.
• Adjust dose of the first dose of chemotherapy to the patient’s creatinine clearance.
• Maintain hemoglobin levels ≥12 g/dL with erythropoietin.
• Use hemopoietic growth factors prophylactically in patients aged ≥70 receiving moderately
toxic chemotherapy (eg, CHOP, cyclophosphamide/doxorubicin, carboplatin/paclitaxel).
• Institute timely and aggressive fluid resuscitation for mucositis.
Several recommendations have
been made to ameliorate the toxicity of chemotherapy in older cancer patients (Table 6).50 The decline
in glomerular filtration rate (GFR)
is one of the most common and
consistent changes in aging.3 In a
retrospective analysis, Gelman and
Taylor44 compared the toxicity and
effectiveness of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in women aged 65
and older and in younger women.
In the older group, the doses of
methotrexate and cyclophosphamide were adjusted to the
patient’s creatinine clearance. The
authors reported that the therapeutic response was similar in the two
age-groups, but the incidence of
myelodepression was lower for the
older women. This study represents level II evidence of the benefits of dose adjustment for CMF in
older patients. Can this conclusion
be extended to other treatment
regimens and to drugs with complex pharmacology (eg, idarubicin,
which is metabolized to idarubicinol, an active alcohol excreted
through the kidneys)?50 Which formula should be used for dose
adjustment and for calculating the
July/August 2000, Vol. 7, No.4
GFR? The answers to these questions cannot be based on either
level I or level II evidence. A further complication is the fact that
the pharmacokinetics of many
drugs is unpredictable.51,52 For
example, Borkowski et al52 showed
that the renal clearance of dichloromethotrexate declines with the
age of the patient, but the total
clearance of the drug declines to a
much lesser extent, thereby suggesting the existence of other pathways of elimination. Thus, the recommendation to adjust the first
dose of treatment to the measured
GFR and the subsequent doses
according to the degree of toxicity
appears reasonable. However, one
could argue for starting with the
full dose, ignoring the GFR, and
making further adjustments according to the toxicity observed.
Supportive Care
The benefits of granulocyte
colony-stimulating factor (G-CSF)
were demonstrated by Zinzani et
al47 in a randomized, prospective
study. These authors found that the
prophylactic addition of G-CSF to a
regimen of cyclophosphamide,
mitoxantrone, vincristine, etoposide, bleomycin, and prednisone
(VNCOP-B) in patients 65 years of
age and older with large-cell nonHodgkin’s lymphoma decreased
the risk of grade III and IV neutropenia by 60% and the risk of
neutropenic infections by 75%.
However, the survival rate of
patients in the two groups was the
same. Whether the indiscriminate
use of growth factors is cost effective when the risk of neutropenic
fever is lower than 40% is debatable. A strong argument in favor of
prophylactic growth factors is the
high treatment-related mortality
rate reported by others48,49,53-55 during the first course of treatment.
Anemia was found to be an
independent risk factor for myelotoxicity,56,57 because a number of
agents are bound to the red blood
cells.50 When anemia is present,
the concentration of circulating
free drugs appears to increase. A
recent randomized, controlled
study of patients younger than age
65 who underwent high-dose
chemotherapy showed that erythropoietin in combination with
G-CSF is more effective that G-CSF
alone in preventing life-threatening neutropenia.58 This study provides level I evidence to support
the use of erythropoietin in combination with G-CSF in anemic
older individuals. Another advantage of erythropoietin is the prevention of fatigue, as reported in
three cohort studies (level II evidence).59-61 It is reasonable to
expect that fatigue may precipitate functional dependence in the
older cancer patient.
Cancer Control 373
The recommendation to utilize
aggressive fluid resuscitation in
older individuals experiencing
grade III or IV mucositis or diarrhea
is based on level IV evidence (ie,
common sense). As the mucositisrelated mortality approached 10%
in the original studies of 5-fluorouracil and high doses of leucovorin in persons aged 65 and older46
and since an effective antidote to
mucositis is not yet available, it
appears reasonable to provide fluid
replacement as soon as toxicity
becomes evident.
A comprehensive geriatric
assessment (CGA) proved effective
in randomized, controlled studies
of the general geriatric population
(level I evidence) in preventing
dependence,62 falls,63 and delirium.18 A CGA also may be beneficial for older patients with cancer
as a tool to recognize the frail
patient, manage coexistent conditions, provide adequate social support, and predict quality of life and
functional reserve. Ongoing trials
may provide adequate evidence of
these benefits.
In addition to special provisions for the administration of
chemotherapy, other age-specific
problems warrant prospective
study in older patients with cancer.
These issues include alternative
forms of adjuvant chemotherapy
for colorectal cancer, the value of
adjuvant chemotherapy in breast
cancer patients aged 70 and older,
the role of amifostine in the prevention of peripheral neuropathy,
and the value of methylphenidate
(Ritalin) in preventing cognitive
complications of chemotherapy.
374 Cancer Control
Conclusions
The study of cancer and aging
provides an excellent model to
study the interaction of evidencebased medicine and common
sense intervention.
Level II evidence supports (1)
estimate of life expectancy based
on function, comorbidity, cognition, and emotional status, (2) staging of functional age based on function and comorbidity into three
stages, from totally independent to
frail, (3) age-related difference in
the behavior of certain neoplasms,
such as acute myeloid leukemia,
large-cell non-Hodgkin’s lymphoma, ovarian cancer, and breast
cancer, and (4) increased risk and
severity of myelodepression and
mucositis in older individuals.
Based on these findings, a number of reasonable recommendations are proposed. Careful perspective study of the implementation of these recommendations
may provide level II evidence of
their value. In some cases, randomized, controlled studies should be
planned, while in other cases, such
as the relatively routine use of
growth factors in patients aged 70
and older, ethical and practical considerations may prevent the conduct of a randomized trial.
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